Hydroxy-gamma-lactones and process therefor



United States Patent $551,123 X -GAMMA-LAT@NES Plliltfillfi THEREFQR Guido lTJarrlelli, lliirsielden, near Basel, Switzerland, and Pauline Haverlrainp liegernann, Dordrecnt, and Pieter Daniel Marines and Anthonie Simon Maria van der Zi jden, Vleartlingen, Netherlands, assignors to Lever Brothers @ompany, New Yorl-r, NEL, a corporation of Maine I' lo Drawing. Filed June 12, lit-62, No. 298,167

3 dilairns. {@l. see-sass) This invention relates to a new class of hym'oxy-garnmalactones and to rnethods ol preparing these compounds.

This is a continuation-in-part of application Serial No. 755,376, filed August 18, 1958, now US. Patent 3,675,998.

new compounds of the invention which for brevity will be termed lactonols have the general formula:

in which R and R are hydrogen or branched-chain or straight-chain alltyl radicals containing from one to five carbon atoms, at least one of them being such an alkyl radical, and R is a hydrocarbon radical selected from the group consisting of alkyl, allcylene, cycloalkyl, cycloalkylalkyl, arallcyl and aralltylene groups having 2 to 9 carbon atoms. Thus R may be for example A preferred class or lactonols according to the invention is the class of -alkyl-5hydroXy-3,4-dirnethyl-2,5-dihydro-iurane-Z-ones in which the S-alkyl radical has 4 t0 7 carbon atoms. Also of importance are the corresponding 3,4-dietl1yl and 3,4-dibutylhon1ologues and the S-alkyl- 5 hydroxy 3,4 dimethyl 2,5 dihydrofurane-2-ones in which the 5 allzyl radical is a branched radical having 5 carbon atoms and the corresponding compounds in which the 5-alkyl radical is replaced by an aralkyl radical having 7 to 8 carbon atoms.

An important use of the lactonols of the invention is in the preparation (by dehydration) of lactones of the formula:

CO.CR1IOR2.C(IR4).O

7 is reacted with the 2.?310- riate Gri nard reauent Rnd i P o c) u I: a

where R is as defined above and X is a halogen atom.

For example:

0001211011 130 R MgCl CO.CR1ZCRz-C(OTVIgC1).R3

where R R and R are as defined above, and the addition compound is hydrolysed to convert the OMgCl group to an ()H grou Patented Sept. 2%, E 64 The reaction has to he carried out at low temperatures to +5 Cjand preferably -7 to 90 C.) in order to avoid the reaction of the addition compound with further molecules of the Grignard reagent.

(b) The alkyl-substituted maleic anhydride is reacted with an organo-zinc-halide, R ZnX, or an organo-cadmiuin compound of the formula R CdR (R being as defined above), and the resulting addition product is hydrolysed to convert the organo-metallic group to an -OH group. The reaction between the alkyl maleic anhydride and the zinc alkyl halide or diallryl cadmium may be carried out at temperatures between 70 and 90 C., preferably about 86 C.

The alkyl-substituted maleic anhydrides described above may be prepared by the following methods:

(a) A beta-lteto-carboxylic acid ester R .CG.CH .-CO.OR

is reacted with sodium and an alkyl halide R X, to form the alpha-alkyd derivative which is then treated with sodium cyanide and hydrochloric acid to form the cyanohydrin R C(OH) (CN).CHR ).C0.OR and this is then hydrolysed and dehydrated to remove two molecules of Water from the resultinghydroxy acid (b) A chlorolrctone of the formula R(.CO.CH(R )Cl is treated with sodium cyanide, the resulting cyano compound R CQCEHR LCN is treated with hydrocyanic acid in the presence of acetic anhydride to form the dicyano acetic ester CH .CO.O.C(R )(CN).CH(R ).CN which is then hydrolysed and dehydrated to form the alkylsubstituted anhydride desired.

(c) An alpha-bromo carboxylic acid ester necnt'n ycooa is reacted with a beta-lceto carboxylic ester,

R' .CO.CH .CO.OR

where R' is an R group as defined above minus the first CH group, to form the reaction product which is then treated with sodium amalgam, hydrolysed and dehydrated to the desired alkyl-substituted anhydride. Examples 1 to 6 below, in which the constitution of the lactonols concerned is defined by the groups R R and R in the general formulae for these classes of substance given above, illustrate the preparation of lactonols according to the invention.

EXAMPLE 1 This example illustrates the preparation of certain 3,4- dimethyl-S-hydroxy-Salkyl-2,5-dihydro furane 2 ones in which the S-alkyl group is an n-alkyl radical.

The starting materials used were 2,3-dimethyl-n1aleic anhydride and an n-ainyl magnesium bromide, the alkyl group being either ethyl, n-propyl or its higher homologues up to n-heptyl.

150 cc. of a solution of the n-alkyl magnesium bromide in ether, containing 9.15 mol. of the bromide and having a tempe ature of about 20 C. was added in 1 /2 hour to a SGlllLlOll of 0.13 mol. of 2,3-dimethyl-rnaleic anhydride in 156 cc. toluene kept at a temperature of 70 C. The solution was kept at this temperature for one hour, arter which the reaction mixture was allowed to Warm up to -l0 C. At this temperature cc. of 2.20% aqueous solution of NH Cl were added. Two layers were obtained, an aqueous layer, which was washed once with a small quantity of toluene, and a toluene layer, to which was added the forernentioned small quantity of toluene used for washing the aqueous layer. This toluene fraction was dried over anhydrous sodium sulphate. After Table II below.

3 distilling off the solvent under vacuum (about 30 mm.) the crude lactonol thus obtained was fractionated under vacuum.

The characteristics of the pure lactonols are given in Table I below. In these compounds R and R are methyl groups and the R groups are n-alkyl radicals of the formulae given in column 1 of the table.

Table 1 LA CTONOLS B.P., C./ U.V. max

Ra mm. 11 in petr ether, x

EXAMPLE 2 This example illustrates the preparation of 3,4-dimethyl-S-hydroxy-S-aralkyl-Z,S-dihydro-furane-Z-ones.

The process was carried out as in Example 1 except that the starting materials used were 2,3-dimethyl-maleic anhydride, phenylmethyl magnesium bromide and 2- phenyl ethyl magnesium bromide.

The characteristics of the pure lactonols are given in the Table III below. In these compounds R and R are methyl groups and the R groups are as defined in column 1 of the table.

Table III LACTON OLS Ra M.P., C. U.V. max. in

petr. ether,

CuHa.CH2.CH2 92. 5 216 CoH5.CH2 76 217 EXAMPLE 4 This example illustrates the preparation of 3,4-diethyl- S-hydroxy-S-n-butyl-Z,S-dihydro-furane-Z-one, and certain homologues.

The process was carried out as in Example 1 except that the starting materials used were 2,3-diethyl-maleic anhydride and an n-alkyl magnesium bromide, the alkyl group being either n-butyl, n-pentyl or n-hexyl.

The characteristics of the pure lactonols are given in the Table IV below. R and R are ethyl groups and the R groups are unbranched acyclic radicals as defined in column 1.

Table IV LAGTONOLS U.V. max.

Rs B.P., O./mm. 121, in petr.

ether, A

EXAMPLE 5 This example illustrates the preparation of a mixture of 3- and 4-methyl-5-hydroxy-S-n-pentyl-2,5-dihydrofurane-Z-ones.

The process was carried out as in Example 1 except that the starting materials used were methyl-maleic anhydride and rr-pentyl magnesium bromide.

The mixture of pure lactonols boiled at 126 C. under 0.22 mm, was of refractive index n =1.4818 and showed a U.V. maximum in petroleum ether at \=211.

EXAMPLE 6 This example illustrates the preparation of 3,4-di-nbutyl-S-hydroxy-5-pentyl-2,S-dihydrO-furane-Z-one.

The process was carried out as in Example 1 except that the starting materials used were 2,3-dibutyl-Inaleic anhydride and n-pentyl magnesium bromide.

The lactonol boiled at l50155 C. under 0.2 mm. and was of refractive index n =1.4690.

EXAMPLE 7 This example illustrates the preparation of the 3,4-dimethyl-S-n-alkyl-Z,5-dihydro-furane-2-ones from 2,3-dimethylmaleic anhydride and the appropriate di(n-alkyl) cadmium. The latter was prepared from the n-alkyl magnesium bromide as follows:

To 0.3 mol. of 11-8lliYl magnesium bromide 0.15 mol. of cadmium chloride was added while cooling. Subsequently the reaction mixture was refluxed until the alkyl magnesium bromide could no longer be detected. To this end the following, so-called Gilman checking test was carried out by mixing with 1-1.5 cc. of the reaction m xture an equal volume of 1% of Michlers ketone in dry benzene, after which 1 cc. of water and a few drops of a 2% iodine solution in glacial acetic were added. If alkyl magnesium bromide was present, a characteristic greenishblue colour was observed.

As soon as the Gilman test gave negative results, 400 cc. of dry benzene was added to the reaction mixture which was then distilled until the issuing vapours had a temperature of C. At that point another 400 cc. of benzene was added. The contents of the flask were brought to the boil (about C.) and dimethyl maleic anhydride was slowly added with stirring. After the reaction the cadmium Grignard complex was hydrolysed with a 10% sulphuric acid solution. The aqueous layer was washed once more with benzene and the combined fractions were subsequently shaken three times with a 10% sodium carbonate solution and then with water, until no longer alkaline. (This purification is necessary to remove traces of anhydride.) After drying over anhydrous sodium sulphate and removal of solvent under a vacuum of 30 mm., the crude lactonol left behind was fractionated.

EXAMPLE 8 In this example 3,4-dimethyl-S-hydroxy-S-n-pentyl-2,5- dihydro-furane-2-one was made from dimethyl maleic anhydride and n-pentyl zinc chloride.

The process was carried out as in Example 1 but substituting for the Grignard reagent the corresponding proportion of n-pentyl zinc chloride, bringing the reagents together at room temperature and heating to 80 C. to effect the reaction.

The lactonols of the invention, besides being useful for the preparation of the corresponding lactones, also provide a new series of metal-sequestering agents.

We claim:

1. 3,4-dimethyl-5-cyclohexyl-S-hydroxy 2,5 dihydrofurane-Z-one.

2. 3,4-dimethyl 5 cyelohexylmethyl-5-hydroXy-2,5- dihydro-furane-2-one.

3. A process for preparing a gamma-hydroxy alpha, beta-unsaturated garnma-lactone comprising reacting together a maleic anhydride of the formula With an addition reagent selected from the group consisting of R MgX, RgZHX and R CdR the reaction being eiiected by bringing the reactants into contact, at a temperature from -95 C. to 5 C. when R MgX is the addition reagent and at a temperature from 70 C. to 90 C. when R ZnX and R CdR are the addition reagents, in an inert solvent; hydrolyzing the resulting ad- 5 dition product to form thereby a gamma-hydroxy alpha,

beta-unsaturated gamma-lactone of the formula and recovering the garnrnahydroxy alpha,beta-unsatu rated gamma-lactone by separating the resulting aqueous layer from the solvent layer, drying the solvent layer and removing the solvent from the gamma-hydroxy alpha, beta-unsaturated ganima-lactone; Where R and R are radicals selected from the group consisting of hydrogen and unsubstituted alkyl having 1 to 5 carbon atoms, at least one of said R and R radicals being such alkyl; R is a hydrocarbon radical selected from the group consisting of unsubstituted alkyl having 2 to 7 carbon atoms, unsubstituted alkylene having 4 carbon atoms, unsubstituted cycloalkyl having 6 carbon atoms, unsubstituted cycloalkylalkyl having 7 carbon atoms, unsubstituted aralkyl having 7 to 8 carbon atoms and unsubstituted araikylene having 9 carbon atoms; and X is a halogen selected from the group consisting of chlorine and bromine.

References Cited in the file of this patent UNITED STATES PATENTS 2,374,563 Reichel Apr. 24, 1945 UNITED STATES PATENT OFFICE CERTHHCATE OF CORRECTHNN Patent No, 3 151,l28 September 29 -1964 Guido Lardelli et a1 It is hereby certified that error appears in the above numbered pat ent reqiiring correction and that the said Letters Patent should read as corrected below.

Column 2 line 22, for "R c(oE)](cN)..cHE )"0,011" read R C(OH)(CN),CH(R2),CO.OR line 26, for "R(.CO.CH(R2)Cl read R ,CO.CH(R )C1 same column 2 line 46 after "by" insert defining Signed and sealed this 16th day of February 1965 (SEAL) IXttest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer v Commissioner of Patents 

1. 3,4-DIMETHYL-5-CYCLOHEXYL-5-HYDROXY-2,5-DIHYDROFURANE-2-ONE. 